tbuckley/cabot-search huggingface dataset:
Bispecific antibodies in cancer therapy: Target selection and regulatory requirements
Authors: Yanze Sun, Xinmiao Yu, Xiao Wang, Kai Yuan, Gefei Wang, Lingrong Hu, Guoyu Zhang, Wenli Pei, Liping Wang, Chengliang Sun, Peng Yang
Journal: Acta Pharmaceutica Sinica B (2023)

In recent years, the development of bispecific antibodies (bsAbs) has been rapid, with many new structures and target combinations being created. The boom in bsAbs has led to the successive issuance of industry guidance for their development in the US and China. However, there is a high degree of similarity in target selection, which could affect the development of diversity in bsAbs. This review presents a classification of various bsAbs for cancer therapy based on structure and target selection and examines the advantages of bsAbs over monoclonal antibodies (mAbs). Through database research, we have identified the preferences of available bsAbs combinations, suggesting rational target selection options and warning of potential wastage of medical resources. We have also compared the US and Chinese guidelines for bsAbs in order to provide a reference for their development.
The epigenetic regulatory mechanisms of ferroptosis and its implications for biological processes and diseases
Authors: Molin Yang, Hanshen Luo, Xin Yi, Xiang Wei, Ding‐Sheng Jiang
Journal: MedComm (2023)

Abstract Ferroptosis is a form of regulated cell death triggered by the iron‐dependent peroxidation of phospholipids. Interactions of iron and lipid metabolism factors jointly promote ferroptosis. Ferroptosis has been demonstrated to be involved in the development of various diseases, such as tumors and degenerative diseases (e.g., aortic dissection), and targeting ferroptosis is expected to be an effective strategy for the treatment of these diseases. Recent studies have shown that the regulation of ferroptosis is affected by multiple mechanisms, including genetics, epigenetics, posttranscriptional modifications, and protein posttranslational modifications. Epigenetic changes have garnered considerable attention due to their importance in regulating biological processes and potential druggability. There have been many studies on the epigenetic regulation of ferroptosis, including histone modifications (e.g., histone acetylation and methylation), DNA methylation, and noncoding RNAs (e.g., miRNAs, circRNAs, and lncRNAs). In this review, we summarize recent advances in research on the epigenetic mechanisms involved in ferroptosis, with a description of RNA N 6 ‐methyladenosine (m 6 A) methylation included, and the importance of epigenetic regulation in biological processes and ferroptosis‐related diseases, which provides reference for the clinical application of epigenetic regulators in the treatment of related diseases by targeting ferroptosis.
Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression
Authors: Xiyue Shen, Kai Luo, Juntao Yuan, Junling Gao, Bingqing Cui, Zhuoran Yu, Zhongbing Lu
Journal: Acta Pharmaceutica Sinica B (2023)

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an important regulator of plasma asymmetric dimethylarginine (ADMA) levels, which are associated with insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD, we used hepatocyte-specific Ddah1-knockout mice (Ddah1HKO) to examine the progress of high-fat diet (HFD)-induced NAFLD. Compared to diet-matched flox/flox littermates (Ddah1f/f), Ddah1HKO mice exhibited higher serum ADMA levels. After HFD feeding for 16 weeks, Ddah1HKO mice developed more severe liver steatosis and worse insulin resistance than Ddah1f/f mice. On the contrary, overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice. RNA-seq analysis showed that DDAH1 affects NF-κB signaling, lipid metabolic processes, and immune system processes in fatty livers. Furthermore, DDAH1 reduces S100 calcium-binding protein A11 (S100A11) possibly via NF-κB, JNK and oxidative stress-dependent manner in fatty livers. Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1HKO mice. In summary, our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice. Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy.
Unmet Clinical Needs in the Management of Idiopathic Multicentric Castleman Disease: A Consensus-based Position Paper From an ad hoc Expert Panel
Authors: Pier Luigi Zinzani, Marco Paulli, Luca Arcaini, Emanuel Della Torre, Simone Ferrero, Amalia Figuera, Ferdinando Frigeri, Maurizio Martelli, Elena Sabattini, Riccardo Scarpa, Giovanni Barosi
Journal: HemaSphere (2023)

Castleman disease describes a group of heterogeneous clinicopathological disorders now included in the tumor-like lesions with B-cell predominance of the World Health Organization classification. Managing idiopathic multicentric Castleman disease (iMCD) is challenging, because few systematic studies or comparative randomized clinical trials have been conducted. International, consensus evidence-based guidelines for iMCD were published in 2018, but gaps in the therapeutic options for difficult-to-treat patients, who do not respond to siltuximab and other conventional therapies, still exist. This article presents the results of group discussion among an ad hoc constituted Panel of Italian experts to identify and address unmet clinical needs (UCNs) in managing iMCD. Recommendations on the appropriateness of clinical decisions and proposals for new research concerning the identified UCNs were issued through formalized multiple-step procedures after a comprehensive analysis of the scientific literature. The following key UCNs were addressed: strengthening the diagnostic certainty in iMCD patients before planning first-line therapy; management of siltuximab therapy; choice and management of immune-modulating, or chemotherapy agents in patients resistant/intolerant to siltuximab therapy. While most of the conclusions reached by the Panel are consistent with the existing guidelines, some alternative therapeutic options were stressed, and the discussion contributed to bringing forth the issues that need further investigation. Hopefully, this comprehensive overview will improve the practice of iMCD and inform the design and implementation of new studies in the field.
Effect of Initial Combination Therapy With Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, and Metformin on Glycemic Control in Patients With Type 2 Diabetes
Authors: Barry J. Goldstein, Mark N. Feinglos, Jared K. Lunceford, Jeremy Johnson, Debora E. Williams-Herman
Journal: Diabetes Care (2007)

OBJECTIVE—To assess the efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control on diet and exercise. RESEARCH DESIGN AND METHODS—In a 24-week, randomized, double-blind, placebo-controlled, parallel-group study, 1,091 patients with type 2 diabetes and A1C 7.5–11% were randomized to one of six daily treatments: sitagliptin 100 mg/metformin 1,000 mg (S100/M1000 group), sitagliptin 100 mg/metformin 2,000 mg (S100/M2000 group), metformin 1,000 mg (M1000 group), metformin 2,000 mg (M2000 group) (all as divided doses administered twice daily [b.i.d.]), sitagliptin 100 mg q.d. (S100 group), or placebo. Patients who had an A1C &amp;gt;11% or a fasting glucose value &amp;gt;280 mg/dl after the run-in period were not eligible to be randomized; these patients could participate in an open-label substudy and were treated with S100/M2000 for 24 weeks. RESULTS—The mean baseline A1C was 8.8% in the randomized patients. The placebo-subtracted A1C change from baseline was −2.07% (S100/M2000), −1.57% (S100/M1000), −1.30% (M2000), −0.99% (M1000), and −0.83% (S100) (P &amp;lt; 0.001 for comparisons versus placebo and for coadministration versus respective monotherapies). The proportion of patients achieving an A1C &amp;lt;7% and &amp;lt;6.5% was 66 and 44%, respectively, in the S100/M2000 group (P &amp;lt; 0.001 vs. S100 or M2000). For the open-label cohort (n = 117; baseline A1C 11.2%) treated with S100/M2000, the within-group mean A1C change from baseline was −2.9%. The incidence of hypoglycemia was low (0.5–2.2%) across active treatment groups and not significantly different from that in the placebo group (0.6%). The incidence of gastrointestinal adverse experiences was similar for coadministration therapies compared with their respective metformin monotherapy. CONCLUSIONS—The initial combination of sitagliptin and metformin provided substantial and additive glycemic improvement and was generally well tolerated in patients with type 2 diabetes.
Hypertension in Pregnancy
Authors: Jane F. Desforges, F. Gary Cunningham, Marshall D. Lindheimer
Journal: New England Journal of Medicine (1992)

THERE have been several important developments related to hypertension in pregnancy since this topic was reviewed in the Journal in 1985.1 These include observations that may help to explain, prevent, and treat the dangerous conditions of preeclampsia and eclampsia. In the recent report of the Working Group on High Blood Pressure in Pregnancy, convened by the National High Blood Pressure Education Program of the National Heart, Lung, and Blood Institute,2 obstetricians and internists reached agreement, perhaps for the first time, on a number of controversial issues. In this article, we focus on conflicts about the management of preeclampsia. Because the . . .
Efficacy and Safety of Rivaroxaban for Postoperative Thromboprophylaxis in Patients After Bariatric Surgery
Authors: Dino Kröll, Philipp C. Nett, Nikki Rommers, Yves Borbély, Fabian Deichsel, Antonio Nocito, Jörg Zehetner, Ulf Kessler, Yannick Fringeli, Lorenzo Alberio, Daniel Candinas, Guido Stirnimann
Journal: JAMA Network Open (2023)

Importance Venous thromboembolism (VTE) is a leading cause of morbidity and mortality after bariatric surgery. Clinical end point studies on thromboprophylaxis with direct oral anticoagulants in patients undergoing bariatric surgery are lacking. Objective To assess the efficacy and safety of a prophylactic dose of 10 mg/d of rivaroxaban for both 7 and 28 days after bariatric surgery. Design, Setting, and Participants This assessor-blinded, phase 2, multicenter randomized clinical trial was conducted from July 1, 2018, through June 30, 2021, with participants from 3 academic and nonacademic hospitals in Switzerland. Intervention Patients were randomized 1 day after bariatric surgery to 10 mg of oral rivaroxaban for either 7 days (short prophylaxis) or 28 days (long prophylaxis). Main Outcomes and Measures The primary efficacy outcome was the composite of deep vein thrombosis (symptomatic or asymptomatic) and pulmonary embolism within 28 days after bariatric surgery. Main safety outcomes included major bleeding, clinically relevant nonmajor bleeding, and mortality. Results Of 300 patients, 272 (mean [SD] age, 40.0 [12.1] years; 216 women [80.3%]; mean body mass index, 42.2) were randomized; 134 received a 7-day and 135 a 28-day VTE prophylaxis course with rivaroxaban. Only 1 thromboembolic event (0.4%) occurred (asymptomatic thrombosis in a patient undergoing sleeve gastrectomy with extended prophylaxis). Major or clinically relevant nonmajor bleeding events were observed in 5 patients (1.9%): 2 in the short prophylaxis group and 3 in the long prophylaxis group. Clinically nonsignificant bleeding events were observed in 10 patients (3.7%): 3 in the short prophylaxis arm and 7 in the long prophylaxis arm. Conclusions and Relevance In this randomized clinical trial, once-daily VTE prophylaxis with 10 mg of rivaroxaban was effective and safe in the early postoperative phase after bariatric surgery in both the short and long prophylaxis groups. Trial Registration ClinicalTrials.gov Identifier: NCT03522259
Plant-derived single domain COVID-19 antibodies
Authors: Andrew M. Shen, Obeid M. Malekshah, Natalia Pogrebnyak, Tamara Minko
Journal: Journal of Controlled Release (2023)

Data show a decrease in the risk of hospitalization and death from COVID-19. To date, global vaccinations for SARS-CoV-2 protections are underway, but additional treatments are urgently needed to prevent and cure infection among naïve and even vaccinated people. Neutralizing monoclonal antibodies are very promising for prophylaxis and therapy of SARS-CoV-2 infections. However, traditional large-scale methods of producing such antibodies are slow, extremely expensive and possess a high risk of contamination with viruses, prions, oncogenic DNA and other pollutants. The present study is aimed at developing an approach of producing monoclonal antibodies (mAbs) against SARS-CoV-2 spike (S) protein in plant systems which offers unique advantages, such as the lack of human and animal pathogens or bacterial toxins, relatively low-cost manufacturing, and ease of production scale-up. We selected a single N-terminal domain functional camelid-derived heavy (H)-chain antibody fragments (VHH, AKA nanobodies) targeted to receptor binding domain of SARS-CoV-2 spike protein and developed methods of their rapid production using transgenic plants and plant cell suspensions. Isolated and purified plant-derived VHH antibodies were compared with mAbs produced in traditional mammalian and bacterial expression systems. It was found that plant generated VHH using the proposed methods of transformation and purification possess the ability to bind to SARS-CoV-2 spike protein comparable to that of monoclonal antibodies derived from bacterial and mammalian cell cultures. The results of the present studies confirm the visibility of producing monoclonal single-chain antibodies with a high ability to bind the targeted COVID-19 spike protein in plant systems within a relatively shorter time span and at a lower cost when compared with traditional methods. Moreover, similar plant biotechnology approaches can be used for producing monoclonal neutralizing antibodies against other types of viruses.
Two Hands, One Journey
Authors: Muhammad Hamza Shah
Journal: JAMA Oncology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
The infant gut microbiota: in pursuit of non-protein nitrogen
Authors: Patrick Schimmel, Bernd Stahl, Jan Knol, Clara Belzer
Journal: Gut Microbes (2023)

Diet shapes our gut microbiome from the day we are born. The contribution of dietary non-protein nitrogen to normal and healthy nitrogen cycling in the infant gut is scarcely described. Herein, we review in vitro and in vivo findings that show the impact of Human Milk Nitrogen (HMN) on the gut microbiota that colonizes the gut in early human life. We describe that several non-protein nitrogen sources, that include creatine, creatinine, urea, polyamines and free amino acids, are key in establishing the bifidobacterium-dominated microbiome and thus are bifidogenic. Furthermore, several parts of HMN-related metabolism are associated with a healthy infant gut and commensal microbiota. We illustrate an overlap and great diversity in accessibility of HMN by large parts of the infant gut microbiota. This review nonetheless shows the importance of research on HMN and its effects on the activity and composition of the infant gut microbiota and its potential effect on early life infant health.
Tucatinib Plus Trastuzumab and Capecitabine for ERBB2 (HER2)-Positive Metastatic Breast Cancer With Brain Metastases
Authors: Dun-Chang Mo, Peng-Hui Luo, Jian-Feng Huang
Journal: JAMA Oncology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Association of Timing of Moderate-to-Vigorous Physical Activity With Changes in Glycemic Control Over 4 Years in Adults With Type 2 Diabetes From the Look AHEAD Trial
Authors: Jingyi Qian, Qian Xiao, Michael P. Walkup, Mace Coday, Melissa L. Erickson, Jessica Unick, John M. Jakicic, Kun Hu, Frank A.J.L. Scheer, Roeland J.W. Middelbeek
Journal: Diabetes Care (2023)

OBJECTIVE We aimed to determine the association of the time-of-day of bout-related moderate-to-vigorous physical activity (bMVPA) with changes in glycemic control across 4 years in adults with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS Among 2,416 participants (57% women; mean age, 59 years) with 7-day waist-worn accelerometry recording at year 1 or 4, we assigned bMVPA timing groups based on the participants’ temporal distribution of bMVPA at year 1 and recategorized them at year 4. The time-varying exposure of bMVPA (≥10-min bout) timing was defined as ≥50% of bMVPA occurring during the same time period (morning, midday, afternoon, or evening), &amp;lt;50% of bMVPA in any time period (mixed), and ≤1 day with bMVPA per week (inactive). RESULTS HbA1c reduction at year 1 varied among bMVPA timing groups (P = 0.02), independent of weekly bMVPA volume and intensity. The afternoon group had the greatest HbA1c reduction versus inactive (−0.22% [95%CI −0.39%, −0.06%]), the magnitude of which was 30–50% larger than the other groups. The odds of discontinuation versus maintaining or initiating glucose-lowering medications at year 1 differed by bMVPA timing (P = 0.04). The afternoon group had the highest odds (odds ratio 2.13 [95% CI 1.29, 3.52]). For all the year-4 bMVPA timing groups, there were no significant changes in HbA1c between year 1 and 4. CONCLUSIONS bMVPA performed in the afternoon is associated with improvements in glycemic control in adults with diabetes, especially within the initial 12 months of an intervention. Experimental studies are needed to examine causality.
The evolving role of lenvatinib at the new era of first-line hepatocellular carcinoma treatment
Authors: Landon L. Chan, Stephen L. Chan
Journal: Clinical and Molecular Hepatology (2023)

Emergence of multi-targeted kinase inhibitors (MTIs) and immune checkpoint inhibitors (ICI) have changed the landscape of management in hepatocellular carcinoma (HCC). Combination therapy involving ICI has superseded sorafenib as the first-line treatment option for advanced HCC due to their superior response rates and survival benefits based on recently published phase III trials. However, the role of first-line lenvatinib remains uncertain as no prospective trials have compared its efficacy with ICI in advanced HCC. Several retrospective studies have shown that first-line lenvatinib may not be inferior to ICI combination. Indeed, a growing body of evidence suggests that ICI treatment is associated with inferior treatment outcome in non-viral HCC patients, questioning the supremacy of ICI treatment in all patients and rendering first-line lenvatinib as a potential preferred treatment option. Furthermore, in high-burden intermediate-stage HCC, accumulating evidence supports first-line lenvatinib, or in combination with transarterial chemoembolization (TACE), as a preferred treatment option over TACE alone. In this Review, we describe the latest evidence surrounding the evolving role of first-line lenvatinib in HCC.
Letter to the Editor: Machine perfusion and acute rejection: Not as simple as it seems—The influence of retransplantation
Authors: Desley AH Neil, Angus Hann, M Thamara PR Perera
Journal: Hepatology (2023)

1Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, Birmingham, UK 2Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK 3Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK Financial support and sponsorship: none Abbreviations: NMP normothermic machine perfusion Correspondence Prof Desley Neil, Department of Cellular Pathology, Level -1, Queen Elizabeth Hospital Birmingham, Birmingham, UK. B15 2GW. Email: [email protected]